Atherosclerosis is a progressive disease characterized by the thickening, hardening and loss of elasticity of inner artery walls. It is the most common cause of morbidity and mortality in the western world, surpassing any other single degenerative disease. In the United States and most other developed countries, atherosclerosis is the leading cause of illness and death. Atherosclerosis caused almost 870,000 deaths in 2005—almost twice as many as cancer caused and 9 times as many as injuries caused.    The following conditions have been linked to atherosclerosis:
Coronary artery disease
Cerebrovascular disease
Kidney disease leading to kidney failure and dialysis
Peripheral vascular disease
The fundamental pathology of vascular disease is an abnormal accumulation of cells within the subintimal space below the surface of the endothelial cell lining, resulting in a decrease in lumen size and tissue perfusion.
With narrowing, atherosclerosis usually does not produce symptoms until the interior of an artery is narrowed by more than 70%. The first symptom of a narrowed artery may be pain or cramps at times when blood flow cannot keep up with the tissues' need for oxygen. For instance, during exercise, a person may feel chest pain because the oxygen supply to the heart is inadequate. While walking, a person may feel leg cramps (intermittent claudication) because the oxygen supply to the leg muscles is inadequate. If the arteries supplying one or both kidneys become narrowed, kidney failure or dangerously high blood pressure can result. If the arteries supplying the heart (coronary arteries) are blocked, a heart attack can result. Blockage in the arteries supplying the brain can causes a stroke. Blockage of the arteries in the legs can cause gangrene of toe, foot, or leg.    The risk factors for atherosclerosis include:    Smoking: The risk of atherosclerosis and related complications is 1.8 times higher in smokers. People who quit using tobacco have only half the risk of those who continue to use tobacco-regardless of how long they smoked before quitting. Quitting also decreases the risk of illness and death in people who have peripheral arterial disease. The benefits of quitting tobacco use begin immediately and increase with time.    Diabetes Mellitus: The risk of developing atherosclerosis is 2 to 6 times higher for people with diabetes, particularly women. These people also tend to develop atherosclerosis at an earlier age and more extensively than do people who do not have diabetes. Control of blood pressure in this group reduces the risk. Glycemic control is good for other complications of diabetes, has no effect on atherosclerosis.    Obesity: Obesity, Particularly abdominal (truncal) obesity, increases the risk of atherosclerosis.    Cholesterol levels: Total cholesterol and LDL cholesterol level are other important modifiable risk factors. Lowering high LDL cholesterol levels through the use of drugs like statins can significantly reduce the risk of morbidity and mortality related to atherosclerosis. The risk is decreased when the LDL cholesterol level is below 130 mg/dl (3.4 mmol/L). In high-risk people, such as those who have diabetes or who already have severe atherosclerotic disease like heart attacks, stroke, or bypass surgery, LDL cholesterol should be below 70 mg/dL (1.8 mmol/L) The desired level of total cholesterol is 140 to 200 mg/dL (3.6 to 5.2 mmol/L).    Blood Pressure: Blood pressure is a risk factor for atherosclerosis related morbidity and mortality e.g. heart attack and stroke. The risk of atherosclerotic cardiovascular disease starts increasing when blood pressure levels are above 110/75 mmHg. Reducing high blood pressure clearly lowers risk. This is in spite of the fact that blood pressure above 140/90 mm of Hg is considered high. The lowering of blood pressure reduces the risk of atherosclerosis related problems in hypertensives as well as nonhypertensives in a similar way. The prophylactic effect is proportional to no. of drugs (one vs two in Progress trial) used to manage B.P.    Anti-platelet agents: People who are at high risk for atherosclerosis also may benefit from taking aspirin or other anti platelet drugs. Aspirin benefit is identical with low as well as high dosage.    Atherosclerosis management in general involves multiple drugs like lipid lowering, blood pressure lowering (more than one), platelet aggregation inhibitors and needs to be taken for regular extended of periods. However there are problems associated with multiple medicines when taken for a long durations.    a) adherence: Unfortunately, adherence may fall as number of drug increases. Swallowing of multiple tablets is likely to lead in non adherence to dosing schedule. It is reported that about 25% medicines when prescribed for long-term conditions, are not taken as directed. Increased numbers of medicines also increase nonadherence.            Reducing pill burden improves adherens (Arch Intern Med. 2005; 165:1147-1152). Improvements in adherence have been seen in a single pill combination of atorvastatin and amlodipine versus a two-pill combination. In a retrospective analysis of pharmacy claims data, this single pill strategy was associated with a two- to threefold improvement in likelihood of adherence.            b) Compliance: Compliance also becomes an issue with multiple medication usage. The multi-component pharmaceutical composition (MCPC) is useful in improving compliance and adherence to therapy.
Despite the need for multi-component pharmaceutical compositions, they have not been commercialized yet due to their inherent problems associated with such compositions especially with regard with stability, drug-drug interaction leading to changes in pharmacokinetic and pharmacodynamic properties.    Even two drug combinations are met with difficulties.
Some of the known examples of alterations changes in pharmacokinetic and pharmacodynamic parameters seen between two drugs belong to a group of antihypertensives, lipid lowering drugs and or antiplatelet agents.    a. Amlodepine (antihypertensive drug) increases AUC of simvastatin (lipid lowering drug) by 30%.    b. Diltiazem (antihypertensive drug) increases AUC of simvastatin (lipid lowering drug) by two fold.    c. Nisoldipine (antihypertensive drug) increases AUC of telmisartan (antihypertesive drug) by 132%.    d. Verapamil and diltiazem (antihypertensive drugs) are known to increase serum level of atorvastatin, simvastatin, lovastatin, fluvastatin but not of pravastatin and rosuvastatin (Statins).    e. Aspirin (Antiplatelet agent) decreases antihypertensive effect of ACE inhibitors.    f. Aspirin (Antiplatelet agent) decreases effects of diuretics.    g. Aspirin (Antiplatelet agent) may decrease pharmacological effects of spironolactone (diuretics).    h. Aspirin (Antiplatelet agent) decreases hypotensive effects of betablockers.    i. Verapamil (antihypertensive agent) when used with betablockers (antihypertensives) I is known to induce brady-cardia and heart failure.    j. Diltiazem (antihypertensive agent) when used with proparanolol (antihypertensives) is known to induce brady-cardia and heart failure.    k. ACE inhibitor (antihypertensive) when used with beta-blockers (antihypertensive) induces hypotension.    l. Propanolol (antihypertensive) when used with ACE inhibitor (antihypertensive agents), results into increased hyperreactivity.    m. Use of ramipril (ACE inhibitor, antihypertensive) and diuretic are known to induce excessive reduction in blood pressure (hypotension) on initiation of therapy.    n. Amlodepine is known to reduce antiplatelet activity of clopidogrel
Drug-drug interaction also takes place in a formulation due to physical and chemical incompatibility. The physical mixture on intimate mixing resulted in incompatibility. Following are some of the examples:
1) Simvastatin+Ramipril+Aspirin
2) Simvastatin+Ramipril+Hydrochlorothiazide
3) Aspirin+Ramipril+Hydrochlorothiazide
4) Simvastatin, Ramipril, Hydrochlorothiazide and Atenolol
5) Atenolol and Simvastatin
European Patent No. 1611886 A1 relates to a combination of an inhibitor of the renin angiotensin system, optionally an additional antihypertensive agent, a cholesterol lowering agent, a diuretic, and aspirin, which can be administered to prevent cardiovascular disorders. The patent does not address issues relates to about the stability related issues, drug-drug interaction, suitable dosage form having patient compliance. The patent mainly discloses about effects of Ramipril, an inhibitor of the renin angiotensin system in prevention or reduction of a cardiovascular event in a high risk patient with no evidence of left ventricular dysfunction or heart failure, where the cardiovascular event is stroke, cardiovascular death or myocardial infarction. Based on current prosecution status, this patent application is withdrawn in European patent office. The present application is deemed to be withdrawn on 30 Oct. 2009 as per EP register.
European Patent No. 1272220 B1 discloses a pharmaceutical formulation that contains at least two agents that lower blood pressure, having different modes of action, plus an active agent from at least two of: lipid regulating agents; platelet function altering agents; and serum homocysteine lowering agents. It is preferred in this patent application to provide at least some of the drugs in smaller amounts than their customary therapeutic doses. The patent is silent about the stability related issues, drug-drug interaction, method of preparing the composition, pharmacokinetic and pharmacodynamic results. Based on current prosecution status, this patent application is under appeal in European patent office.
An article by N. J. Wald et al. “A Strategy to Reduce Cardiovascular Disease by More Than 80%,” British Medical Journal, Vol. 326, pp. 1419-1423, 2003, advocates the daily prophylactic treatment of everyone over age 55, and everyone with existing cardiovascular disease, with a “Polypill” containing the following six drugs: a drug to lower cholesterol, such as either atorvastatin (10 mg) or simvastatin (40 mg), the combination of three blood pressure lowering drugs from different classes, such as a thiazide; a, Beta-blocker, and an ACE inhibitor, folic acid (0.8 mg), and aspirin (75 mg). The article doesn't discloses the formulation related details, drug-drug interaction, method of preparing the composition, stability related issues.
U.S. Patent application 20050026992 discloses pharmaceutical dosage form for treating or preventing cardiovascular events comprises therapeutic amounts of: a beta-adrenergic receptor antagonist, a diuretic, or both; a cholesterol-lowering agent; an inhibitor of the renin-angiotensin system; and aspirin. This application doesn't discuss about stability of the pharmaceutical dosage form. The patent application is also silent over bioequivalence information. The present prosecution status as per USPTO appears that the patent application has been given final rejection from USPTO examiner.
PCT application WO/2007/098390 A2 discloses new use of darusentan for adjunctive administration with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers, to lower blood pressure in a patient having resistant hypertension. The patent application is mainly related to new use of darusentan. The patent is silent about the stability related issues, drug-drug interaction, suitable dosage form having patient compliance in terms of formulation weight, ease of administration and the like.
U.S. Patent application 20070116756 discloses pharmaceutical dosage form for treating or preventing cardiovascular events comprises therapeutic amounts of: a beta-adrenergic receptor antagonist, a diuretic, or both; a cholesterol-lowering agent; an inhibitor of the renin-angiotensin system; and aspirin. The patent application discloses maximum of four active agents in the formulation. The stability data of Example 1 doesn't disclose the stability of all active agents used in the formulation.
The presence of multiple drugs in a single formulation can lead to various issues including drug-drug interaction. This interaction is evident in following literature.                An article by Shinichiro Nishio et al. “Interaction Between Amlodipine And Simvastatin In Patients With Hypercholesterolemia And Hypertension” Hyprtens Res Vol. 28 No. 3 (2005) pg 223-227 discloses that calcium channel blocker, amlodipine affects the plasma concentration of HMG-CoA reductase inhibitor, simvastatin.        An article by Henry L. Elliott et al. “The Interactions Between Nisoldipine And Two β Adrenoceptor Antagonists—Atenolol And Propranolol” Br. J. Clin. Pharmac. (1991), 32, pg 379-385 discloses that steady state plasma concentrations of both β-adrenoceptor antagonists were significantly altered by the addition of nisoldipine.        An article by Mansoor Rastegarpanah et al. “A New Horizon In Primary Prevention Of Cardiovascular Disease, Can We Prevent Heart Attack By “Heart Polypill”” discloses Polypill has been the subject of great deal of debate. There is no evidence from randomized controlled trials that the treatment would be effective. There are still issues regarding its design, synthesis, pharmacokinetics, pharmacodynamics, bioequivalence, interactions, and evidence of clinical efficacy, adverse effects and safety.        An article by Ivancica et al. “Interaction between Antihypertensives and NSAIDS in primary care: a controlled trial” discloses that NSAIDS like Piroxicam and Ibuprofen markedly blunt the effect of antihypertensive drugs.        
Thus, the presence of many drugs or active agents in a single solid oral composition can lead to various problems related to physical, chemical stability of the dosage form and the drugs. These drugs may react with each other (drug-drug interaction) or the excipients present in the composition and ultimately lead to unstable formulation. Further there are chances that one drug will alter the bioavailability of the other drug.
It is very difficult to adjust the absorption of different active agents from single solid oral composition. Usually in practice, the absorption of one of the active agents may decrease while that of the other one increases. When selecting the pharmaceutical excipients, to be used in a pharmaceutical composition in combination with several active agents, numerous factors have to be considered, e.g., the chemical and physical characteristics of the active agents and excipients, the bioavailabilities of the active agents, the method of preparing the composition, the stability of the composition and the like.
As disclosed in various prior art that combination of multiple active drugs in single formulation leads to drug-drug interaction. Such drug-drug interaction may result in following possibilities in combination of active drugs based on Multi-constituent cardiovascular pill (MCCP) or multi-component pharmaceutical composition (MCPC):                1. Loss of activity of any of active ingredient.        2. Increase in adverse event profile as compared to single active drug included in the composition.        3. Variability in serum level of antihypertensive drugs which is achieved by consumption of a single ingredient or active drug.        4. Reduction in sitting systolic and diastolic B.P. as compared to single ingredient or active drug.        5. Significant differences in heart rate, lipid levels, serum concentration, as compared to single ingredient or active drug.        
Neither of the above-cited patents nor any other publication, of which applicants are aware, describes a solid oral composition which has resolved the above mentioned issues.
Further, in accordance with the recommendations made by the World Health Organization to develop combination products for cardiovascular therapy and test their efficacy in high risk individuals, it is highly desirable to develop combination products using a diverse cardiovascular drug/s including adrenergic blocking agent, a diuretic, a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin.
It is a long-standing need in the pharmaceutical industry to provide stable pharmaceutical composition comprising combination of adrenergic receptor blocking agent, HMG Coenzyme-A reductase inhibitor, renin-angiotensin enzyme inhibitor, diuretic and platelet aggregation inhibitor in a single dosage form with less side effects and more efficacy and better patient compliance as compared to individual active ingredient.